IL-17A exacerbates cisplatin-based resistance of OVCA via upregulating the expression of ABCG2 and MDR1 through Gli1-mediated Hh signaling

Abstract

// Xiulong Niu 1, 2, * , Wenxing Liu 1, * , Yue Wang 3 , Xiaomei Liu 4 , Hongjian Zhang 1 , Zhijun Li 1 , Hongzhao Li 1 , Yoichiro Iwakura 5 , Weimin Deng 1 1 Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Diseases and Microenvironment of Ministry of Education of China, Tianjin Medical University, Tianjin 300070, China 2 Department of Infectious Diseases, Hospital Affiliated to Logistics College of Chinese People’s Armed Police Forces, Tianjin 300162, China 3 Department of Immunology, Logistics College of Chinese People’s Armed Police Forces, Tianjin 300162, China 4 Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, Tianjin 300052, China 5 University Research Administration Center, Tokyo University of Science, Tokyo125-8585, Japan * These authors have contributed equally to this work Correspondence to: Weimin Deng, e-mail: dengweimin@tijmu.edu.cn Keywords: IL-17A, cisplatin, drug-resistance, ovarian cancer, sensitivity Received: October 08, 2015      Accepted: May 04, 2016      Published: July 18, 2016 ABSTRACT The major obstacle of the tumor chemotherapy, including ovarian cancer (OVCA), is drug resistance. However, the relevance of IL-17A with drug-resistance of OVCA has been poorly elaborated. In this study, we used 2 human OVCA cell lines to investigate the effects of IL-17A on cisplatin (CDDP or DDP)-based resistance in OVCA cells and the underlying mechanisms. Meanwhile, IL-17A-deficient mice and ID8 were used to verify the IL-17A’s effects on OVCA chemo-resistance in vivo . Moreover, the relationship between IL-17A level and relevant indices were primarily assessed in ovarian specimens from 55 patients with OVCA. We found that rhIL-17A exacerbated DDP-based resistance of OVCA cells via up-regulating the expression of ABCG2 and MDR1 through Gli1-mediated Hh signal pathway. Animal experiment demonstrated that IL-17A significantly recede DDP-based treatment for ID8 tumor. Similar results were observed in preliminary clinical investigation. Our findings suggest that inhibiting IL-17A/IL-17RA-Gli1 signal may improve the resistance of OVCA to DDP.